Co-crystals and pharmaceutical compositions comprising the same

Abstract

The invention relates to compositions and co-crystals each comprising (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide having the structure: and the co-crystal former salicylic acid. Also within the scope of this invention are methods of making and using the same.

1. A co-crystal comprising (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide and salicylic acid, wherein said co-crystal has X-ray powder diffraction peaks at about 4.43, 7.63, 8.53, 9.63, 12.89, 14.83, 16.29 2-Theta. 
     
     
       2. The co-crystal of  claim 1 , wherein the molar ratio of (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide and salicylic acid is about 1:1. 
     
     
       3. The co-crystal of  claim 2 , having peaks in its DSC thermogram at about 137° C. and 223° C. 
     
     
       4. A co-crystal of the formula ((1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide) m : (CCF) n , wherein CCF is the co-crystal former salicylic acid; m and n, independently, are an integer of 1 to 5; and said co-crystal has X-ray powder diffraction peaks at about 4.43, 7.63, 8.53, 9.63, 12.89, 14.83, 16.29 2-Theta. 
     
     
       5. The co-crystal of  claim 4 , wherein m and n are both 1. 
     
     
       6. A pharmaceutical composition comprising
 a. a co-crystal comprising (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide and the co-crystal former salicylic acid, wherein said co-crystal has X-ray powder diffraction peaks at about 4.43, 7.63, 8.53, 9.63, 12.89, 14.83, 16.29 2-Theta; and 
 b. a diluent, solvent, excipient, carrier, or solubilizing agent. 
 
     
     
       7. The pharmaceutical composition of  claim 6 , wherein the molar ratio of (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3-dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide and the co-crystal former is about 1. 
     
     
       8. A method of making the co-crystal according to  claim 1 , comprising the steps of grinding, heating, co-subliming, co-melting, or contacting in solution (1S,3aR,6aS)-2-[(2S)-2-[[(2S)-2-Cyclohexyl-2-(pyrazine-2-carbonylamino)acetyl]amino]-3,3 -dimethylbutanoyl]-N-[(3S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-1-carboxamide) with salicylic acid to form the co-crystal in solid phase, and optionally isolating the co-crystal formed.